4JMZ

Crystal structure of Cytochrome C Peroxidase W191G-Gateless in complex with N-methyl-1H-benzimidazol-2-amine

Summary for 4JMZ

• Entry DOI: 10.2210/pdb4jmz/pdb
• Related: 1KXM 1KXN 4JM5 4JM6 4JM8 4JM9 4JMA 4JMB 4JMS 4JMT 4JMV 4JMW 4JN0 4JPL 4JPT 4JPU 4JQJ 4JQK 4JQM 4JQN
• Descriptor: Cytochrome c peroxidase, PROTOPORPHYRIN IX CONTAINING FE, N-methyl-1H-benzimidazol-2-amine, ... (4 entities in total)
• Functional Keywords: model system, bulk solvent, ordered waters, docking, ligand binding, oxidoreductase
• Biological source: Saccharomyces cerevisiae (Baker's yeast)
• Total number of polymer chains: 1
• Total formula weight: 33692.25

Authors

Barelier, S.,Fischer, M. (deposition date: 2013-03-14, release date: 2013-05-01, Last modification date: 2024-02-28)

Primary citation

Barelier, S.,Boyce, S.E.,Fish, I.,Fischer, M.,Goodin, D.B.,Shoichet, B.K.
Roles for ordered and bulk solvent in ligand recognition and docking in two related cavities.
Plos One, 8:e69153-e69153, 2013

PubMed Abstract: A key challenge in structure-based discovery is accounting for modulation of protein-ligand interactions by ordered and bulk solvent. To investigate this, we compared ligand binding to a buried cavity in Cytochrome c Peroxidase (CcP), where affinity is dominated by a single ionic interaction, versus a cavity variant partly opened to solvent by loop deletion. This opening had unexpected effects on ligand orientation, affinity, and ordered water structure. Some ligands lost over ten-fold in affinity and reoriented in the cavity, while others retained their geometries, formed new interactions with water networks, and improved affinity. To test our ability to discover new ligands against this opened site prospectively, a 534,000 fragment library was docked against the open cavity using two models of ligand solvation. Using an older solvation model that prioritized many neutral molecules, three such uncharged docking hits were tested, none of which was observed to bind; these molecules were not highly ranked by the new, context-dependent solvation score. Using this new method, another 15 highly-ranked molecules were tested for binding. In contrast to the previous result, 14 of these bound detectably, with affinities ranging from 8 µM to 2 mM. In crystal structures, four of these new ligands superposed well with the docking predictions but two did not, reflecting unanticipated interactions with newly ordered waters molecules. Comparing recognition between this open cavity and its buried analog begins to isolate the roles of ordered solvent in a system that lends itself readily to prospective testing and that may be broadly useful to the community.

PubMed: 23874896
DOI: 10.1371/journal.pone.0069153

Experimental method

X-RAY DIFFRACTION (1.82 Å)